Recent surveys of drug abuse indicate that more people are dependent on marijuana than all other illicit drugs combined. Little is known about factors that contribute to marijuana dependence but genetic factors influencing cannabinoid sensitivity may play a role. Preliminary data presented in this proposal suggest PKCepsilon null mice are more sensitive to cannabinoid compounds in two behavioral measures. These effects may be due to PKCepsilon dependent phosphorylation of the CB1 receptor or of its downstream effector, the N- type calcium channel. This hypothesis is supported by evidence that the CB1 receptor is phosphorylated by an unknown PKC isozyme that decreases its signaling as well as research demonstrating that N-type calcium channels are phosphorylated by PKCepsilon. In this proposal, I will determine if the CB1 receptor is modulated by PKCepsilon by measuring behavioral sensitivity of PKCepsilon deficient mice to cannabinoids and by examining the regulation of adenylyl cyclase activity and N-type calcium channel currents by cannabinoids in PKCepsilon-deficient neurons. These investigations will not only provide insight into a factor that may contribute to marijuana dependence, but will also aid in understanding regulatory mechanisms of the endogenous cannabinoid system.